Background A substantial proportion of patients with AMI are currently considered ineligible for thrombolysis, and reperfusion treatment is frequently not recommended for them. It is not known whether these patients benefit from PCI.

Methods The Stent or PTCA for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Ineligible for Thrombolysis (STOPAMI-3) trial, a randomized, open-label study, included 611 patients with AMI who were ineligible for thrombolysis (lack of ST-segment elevation on the electrocardiogram, late presentation >12 h after symptom onset, and contraindications to thrombolysis). Patients were randomly assigned to receive either coronary artery stenting (n = 305) or PTCA (n = 306). Scintigraphic myocardial salvage index (proportion of the initial myocardial perfusion defect that was salvaged by reperfusion) was the primary end point of the study.

Results A considerable myocardial salvage was achieved with both stenting and PTCA. In patients assigned to receive stenting, the median size of the salvage index was 0.54 (25th and 75th percentiles, 0.29 and 0.87), as compared with a median of 0.50 (25th and 75th percentiles, 0.26 and 0.82) in the group assigned to receive PTCA (p = 0.20). Mortality at six months was 8.2% in the group of patients assigned to receive stenting and 9.2% in the group of patients assigned to receive PTCA (p = 0.69).

Conclusions Patients with AMI who are currently considered ineligible for thrombolysis by conventional guidelines may greatly benefit from primary PCI. The benefit seems to be comparable when a strategy of stenting is compared with a strategy of PTCA in these patients.

Reperfusion therapies reduce the mortality of patients with acute myocardial infarction (AMI) who have been considered eligible for this treatment strategy (1). The key mechanism by which reperfusion improves prognosis in these patients is the salvage of jeopardized myocardium (2). Currently, however, only <30% of the patients with AMI receive reperfusion therapy (3–5). The major reason for the limited use of reperfusion is that >50% of the patients with AMI are considered ineligible for this therapy, mostly due to lack of ST-segment elevation on the electrocardiogram (ECG) or late presentation of the patients after symptom onset (3,5). In fact, the use of thrombolysis has provided no measurable benefit in patients with non–ST-segment elevation myocardial infarction (MI) and in those presenting >12 h after onset of symptoms (1,6–8). Because thrombolysis has been the only reperfusion option evaluated by specifically designed studies, ineligibility for reperfusion is often used instead of the more correct denomination of ineligibility for thrombolysis. Recently, the Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) study also found no benefit with the use of antithrombotics in patients ineligible for reperfusion (9). Although patients deemed ineligible for reperfusion represent a large subset carrying a particularly high risk (10–12), they have remained understudied and without specific treatment guidelines as compared with patients with AMI who are currently treated with reperfusion therapy (13). Percutaneous coronary interventions are superior to thrombolysis in patients with AMI eligible for thrombolysis (14–16), but we still do not know their role in the treatment of ineligible patients. Therefore, the objectives of this study were to evaluate the potential of percutaneous coronary interventions to salvage myocardium in patients with AMI ineligible for thrombolysis and to assess whether coronary stenting is superior to conventional percutaneous transluminal coronary angioplasty (PTCA) in this setting.

Methods

Patients

This study included patients with AMI who were ineligible for thrombolysis and admitted for primary treatment in two university hospitals (Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar, Munich, Germany), in the period from July 1998 to February 2002. The diagnosis of AMI was based on the presence of chest pain lasting ≥20 min associated with typical changes on surface ECG (ST-segment elevation of ≥0.1 mV in ≥2 limb leads or ≥0.2 mV in ≥2 contiguous precordial leads, pathological Q waves, or complete left bundle branch block of new-onset) or elevation of creatinine kinase (CK) and its MB isoenzyme more than twice the upper normal limit. The ineligibility for thrombolysis was defined as the presence of at least one of the following criteria: non–ST-segment elevation infarction, presentation of the patient >12 h from onset of symptoms, and any contraindication to thrombolysis as defined previously (8). Patients were excluded from the study if they arrived to hospital later than 48 h after onset of pain or if they did not provide informed consent for participation in the study. The study protocol was approved by the institutional ethics committee.

Study protocol

After the diagnosis was made, all patients received 500 mg aspirin and 5,000 U heparin intravenously. In addition, they received an intravenous injection of 1,000 MBq 99mTc sestamibi required for the baseline scintigraphic study. Patients were then transferred to the catheterization laboratory immediately, and left ventriculography followed by coronary angiography were performed. Immediately after the decision to perform a percutaneous coronary intervention, the patients were randomly assigned to one of the treatment strategies, coronary stenting or PTCA, by means of sealed envelopes containing a computer-generated randomization sequence. The sequence was generated in two blocks (one for each participating hospital) and was concealed until the intervention was assigned. Opening of the envelopes containing the randomization arm was done by the nurse assisting during the procedure, and all pertinent information (randomization number, randomization arm, and patient's identification data) was immediately recorded. Stenting was allowed in the PTCA group if the result after conventional balloon angioplasty was not optimal (Thrombolysis In Myocardial Infarction [TIMI] flow <3, large dissections or significant residual thrombus, residual diameter stenosis ≥50%). All patients without contraindications were treated with abciximab (ReoPro, Lilly Deutschland GmbH, Bad Homburg, Germany) given as a bolus of 0.25 mg/kg of body weight followed by a continuous infusion of 0.125 μg/kg/min for 12 h and 60 U/kg heparin (up to a maximum of 5,000 U). In the subgroup of patients with contraindications to thrombolysis, abciximab was given when felt to be required by the operator on the basis of the presence of large thrombotic material or suboptimal results of the intervention. Postinterventional antithrombotic therapy consisted of ticlopidine, 250 mg twice a day (initial study period), or clopidogrel, 75 mg for at least four weeks, and aspirin, 100 mg twice a day, indefinitely. No loading doses of ticlopidine and clopidogrel were given. Single photon emission computed tomography study was done within 6 to 8 h after the injection of the radionuclide. Follow-up scintigraphy study was scheduled 7 to 14 days after treatment and done according to the same protocol as in the initial study. The methods used for the radionuclide studies are described in detail previously (15). All measurements were performed in the scintigraphic core laboratory by well-trained operators who were unaware of the assigned therapy. The initial perfusion defect and the size of the infarct (perfusion defect at follow-up study) were calculated. The difference between above two parameters provided the degree of myocardial salvage. Initial perfusion defect, infarct size, and degree of myocardial salvage were expressed as a percentage of the left ventricle (LV). Salvage index was then calculated as the ratio between the degree of myocardial salvage and initial perfusion defect. The mean (±SD) intraobserver and interobserver variations in the measurement of the size of the defect in this laboratory are 2 ± 3% and 2 ± 3% of the LV, respectively. Qualitative and quantitative evaluation of the digital angiograms was performed off-line in the Angiographic Core Laboratory. The automated edge detection system CMS (Medis Medical Imaging Systems, Nuenen, Netherlands) was used for the measurement of angiographic parameters before and after the intervention. During the hospital stay, CK and its MB isoenzyme, hemoglobin, and platelet count were determined before and 8, 16, and 24 h after the treatment, and daily thereafter. After discharge, the assessment of clinical status was made by means of a phone interview at 30 days and follow-up visit at six months or whenever dictated by patient complaints.

Study end points and definitions

The primary end point of the study was salvage index. Secondary end point of the study was mortality during the first six months after randomization. Other adverse events evaluated were: recurrent infarction defined as a typical chest pain, new ST-segment changes, and an increase in CK of at least 50% over the previous trough level in at least two samples reaching ≥240 U/l; stroke with confirmation by computed tomography or magnetic resonance imaging of the head; and major bleeding complications were defined as any bleeding requiring blood transfusion or causing a drop of at least 5 g/dl in hemoglobin. Other events, such as repeat PTCA or need for aortocoronary bypass surgery, were also monitored during the six-month period after randomization.

Statistical analysis

The number of patients included in the study was based on the sample size estimation for our primary end point, salvage index achieved with each therapy. On the basis of our previous experience, we expected the achievement of a salvage index of 0.50 ± 0.39 in the group of stenting. Assuming that the salvage index would be 0.40 in the PTCA group, we estimated that 240 patients would be required in each group for the study to have a power of 80% to detect an absolute difference in the salvage index of 0.10 with a two-sided α value of 0.05. We allowed for the possibility of incomplete scintigraphic studies and included a total of 611 patients in this study.

The data are presented as median (25th, 75th percentiles) or as counts or proportions (%). The differences between the groups were assessed using a two-sided chi-square test or Fisher exact test (whenever an expected cell value was <5) for categorical data, and the nonparametric Wilcoxon rank-sum test for continuous data. Survival analysis was made by applying the Kaplan-Meier method. Differences in survival parameters were assessed for significance by means of the log-rank test. Statistical significance was accepted for a two-tailed p < 0.05. All analyses were performed on the basis of the intention-to-treat principle. According to the same principle, the primary end point of the study was also analyzed in prespecified subsets defined by the reason of ineligibility for thrombolysis, presence of first MI, infarct localization, and complete absence of anterograde flow in the infarct-related coronary artery in the preinterventional angiogram.

Results

Of the 611 patients enrolled in this trial, 305 were randomly assigned to stent and 306 to PTCA. Table 1shows patients demographics, cardiovascular risk factors, and history data, which were comparable between the two groups. Table 2shows the infarct characteristics of the patients, which also were comparable. About 8% of the patients were in Killip class IV. In addition, the ECG on admission of patients with a delayed presentation showed left bundle branch block in 3.3%, pathologic Q-wave in 25.3%, and ST-segment elevation in 71.4% of the cases; 11.8% of the patients in this group had persistent symptoms at admission. Angiographic data shown in Table 3were also not significantly different. Differences were seen in the procedure-related variables: patients of the stent group were treated with a higher balloon pressure and greater balloon-to-vessel ratio, with a final angiographic lumen superior to that achieved in the PTCA group (Table 3). Placement of stent(s) was necessary in 30.4% of the patients in the PTCA group; 90.3% of the patients received abciximab (57.9% of the 121 patients with contraindication to thrombolysis and 98.3% of those with non–ST-segment elevation infarction or with a >12-h delay from onset of symptoms). There were no significant differences in the TIMI flow grade achieved at the end of the procedure. The most common drugs given after the intervention are listed in Table 4; no significant differences were seen between the two groups.

Myocardial salvage

Paired scintigraphic studies that allowed the assessment of the salvage index, primary end point of the trial, were achieved in 501 patients (82% of the entire study population). Figure 1shows an example of successful reperfusion, with scintigraphic and angiographic images before and 10 days after intervention. The scintigraphic data are shown in Table 5. The initial perfusion defect, final infarct size, and degree of myocardial salvage were comparable between the two study arms. Overall, a salvage index of 0.53 (25th, 75th percentiles: 0.27, 0.84) was achieved with primary coronary interventions. The salvage index was 0.54 (0.29, 0.87) in the stent group and 0.50 (0.26, 0.82) in the PTCA group (p = 0.20). When we analyzed the salvage index on the basis of the “per protocol” principle (i.e., after excluding those patients who did not receive the randomly assigned therapy), the salvage index was 0.54 (0.27, 0.87) in the stent group and 0.53 (0.27, 0.83) in the PTCA group (p = 0.50). When we analyzed the salvage index on the basis of the “as treated” principle (i.e., according to the actual treatment received), the salvage index was 0.52 (0.26, 0.86) among patients treated with stenting and 0.53 (0.27, 0.83) among patients treated with PTCA (p = 0.98). Figure 2shows that the mechanical recanalization provides a substantial myocardial salvage in all analyzed subsets without any measurable superiority of stenting over PTCA.

Graph showing the salvage index achieved in various subsets and the differences in the salvage index between the stent group and the percutaneous transluminal coronary angioplasty (PTCA) group. Horizontal bars indicate the 95% confidence interval.

Clinical outcome

During the first 30 days after randomization, 17 patients in the stent group (5.6%) and 15 patients in the PTCA group (4.9%) died (p = 0.71). During this period, six patients in the stent group (2.0%) and four patients in the PTCA group (1.3%) showed angiographically documented target vessel occlusion (p = 0.75, Fisher exact test). Major bleeding was observed in four patients of the stent group (1.3%) and six patients of the PTCA group (2.0%), p = 0.76 (Fisher exact test).

During the six-month period after randomization, 8.2% of the patients in the stent group and 9.2% of those in the PTCA group died, relative risk 0.90 (95 confidence interval, 0.52 to 1.54), p = 0.69. Figure 3shows the six-month survival curves for each group. The combined incidence of death or recurrent MI was 10.5% in either group. Six patients (three in each group) incurred stroke; it was of ischemic origin in five patients and hemorrhagic in one patient. In addition, 2.3% of the patients in the stent group and 2.0% of those in the PTCA group required aortocoronary bypass surgery (p = 0.77); repeat PTCA was performed in 8.2% of the patients in the stent group and 10.5% of those in the PTCA group (p = 0.34).

Six-month survival curves for patients in the stent group and those in the percutaneous transluminal coronary angioplasty (PTCA) group.

Discussion

We assessed myocardial salvage after primary percutaneous coronary interventions, stenting, and PTCA in patients with AMI currently considered ineligible for reperfusion. The major finding of this study is that percutaneous coronary intervention in this subset of patients enables the achievement of a substantial salvage of the myocardium at risk, without any significant difference between the two evaluated approaches: stenting and PTCA.

The majority of patients with AMI are considered ineligible for thrombolysis and, therefore, are not afforded the opportunity for early reperfusion (17,18). These ineligible patients can have significant consequences (19). Although a variety of reasons for not providing reperfusion including older age and female gender has been identified (18), the lack of ST-segment elevation on the ECG of presentation, contraindications to thrombolytic therapy, and a >12-h delay from onset of symptoms are the principal ineligibility criteria admitted by current guidelines (13). Optimal treatment strategy in patients with non–ST-segment elevation infarction has been the subject of a long-standing debate (20). However, increasing recent evidence has proven the superiority of percutaneous coronary interventions over the conservative strategy in these patients (21–23). On the other side, although no one will question the benefit of primary coronary interventions in patients with AMI who present with contraindications to thrombolytic therapy, no specific studies have been dedicated to this category of patients. In a recent randomized trial, patients ineligible for thrombolysis underwent percutaneous coronary intervention and were entered into a registry; however, no outcome data were reported for patients in this registry (24). The present prospective randomized trial demonstrates the considerable potential of the interventional strategy to salvage jeopardized myocardium in patients with AMI without ST-segment elevation or with contraindications to thrombolytic treatment. Both stenting and conventional balloon angioplasty combined with glycoprotein IIb/IIIa inhibition with abciximab in the majority of cases provided comparable myocardial salvage and six-month survival in these patients. Two recent trials compared stenting with PTCA in patients with AMI with ST-segment elevation (25,26). These trials found no significant difference in six-month mortality between the two strategies; however, stenting was associated with a significant reduction in the need for reintervention (25,26). In the present trial, we observed only a trend toward a lower six-month incidence of repeat balloon angioplasty in the stent group. The lack of a bigger difference in favor of stenting in our trial could be explained with a more liberal use of provisional stenting in the PTCA group (30.4% as compared with 14% to 18% in the previous two trials [25,26]).

Patients with AMI arriving to hospital after 12 h from symptom onset represent a relevant medical problem not only because of their large number (3,5)but also because of the dramatic failure of the most common reperfusion therapy, thrombolysis, in these conditions (6,7). Relatively few data on the role of percutaneous coronary interventions in patients with AMI with delayed arrival to hospital have mostly come from observational studies (18). In a series of 139 patients presenting 6 to 48 h after onset of chest pain, a successful primary coronary balloon angioplasty was associated with a lower mortality as compared with failed procedures (27). In a German registry study, 94 of 848 patients with AMI presenting with a >12 h delay were treated with primary balloon angioplasty that was associated with a significant decrease in hospital mortality as compared with those who did not receive reperfusion treatment (28). Similar results were also reported from the National Registry of Myocardial Infarction; in patients presenting late, hospital mortality was lower in those treated with early invasive than in those receiving conservative therapy (29). Both studies cited above were, however, biased in the decision to perform primary coronary interventions; those treated invasively had a lower risk profile than those treated conservatively (28,29). In a prospective randomized trial, 201 patients with AMI ineligible for thrombolytic therapy were randomly assigned to two initial management strategies: invasive and medical (17). Invasive strategy lead to immediate revascularization in 58% of the cases, whereas 37% of the cases assigned to medical treatment also required early revascularization due to recurrent ischemia while in hospital (17). At a median of 21 months, there was no significantly different outcome between the two groups, but separate outcome data regarding the 93 patients presenting with symptoms >6 h in duration were not reported (17). Therefore, our study provides findings that may help to fill the gap in previous investigations on the treatment of AMI: that regarding patients with delayed presentation. Both primary stenting and balloon angioplasty were rewarded with a considerable and comparable myocardial salvage in these patients. Although our trial did not include a control group consisting of a treatment strategy other than percutaneous coronary interventions, our findings strongly support the use of primary invasive approaches for the management of patients with AMI coming to hospital >12 h from onset of symptoms. The reasons for the superiority of the interventional strategy over thrombolysis as also suggested by previous observational data (30)should be sought in the different time-dependence of efficacy of these two methods in restoring myocardial flow. Previous studies have shown that the ability of thrombolysis to fully restore epicardial flow significantly decreases as the time-to-admission interval increases (31,32). Even in cases of successful anterograde restoration of epicardial flow, thrombolytic agents may contribute to impairment of microcirculatory function in addition to the negative effects of the prolonged ischemia (33,34). Primary percutaneous interventions are able to achieve a high rate of full epicardial flow restoration not only in patients presenting early after onset of symptoms (35). We also cannot exclude an additive positive contribution of abciximab to our favorable results in patients with delayed presentation, considering the enhancing effects of this substance on the recovery of myocardial flow (36). Two clinical trials have found a reduced rate of ischemic complications after the use of abciximab as an adjunct therapy to coronary stenting in patients with AMI (37,38). Other investigators were unable to find a significant clinical benefit from abciximab in patients with AMI treated with percutaneous coronary interventions (26).

In conclusion, the results of the present study show that the large group of patients with AMI currently considered ineligible for thrombolysis by conventional guidelines may greatly benefit from primary percutaneous coronary interventions. The benefit seems to be comparable when a strategy of stenting is compared with a strategy of balloon angioplasty in these patients.

Acknowledgements

The authors highly appreciate the invaluable contribution of the medical and technical staffs operating in the coronary care units, nuclear medicine, and catheterization laboratories of the participating institutions.

References

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(2000) Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol36:2056–2063.

(1996) ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation94:2341–2350.

(1999) Relevance of clinical trial results in myocardial infarction to medical practice: comparison of four year outcome in participants of a thrombolytic trial, patients receiving routine thrombolysis, and those deemed ineligible for thrombolysis. Heart81:598–602.

(1999) 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol34:890–911.

(2000) A prospective, randomized trial comparing primary balloon angioplasty with or without abciximab to primary stenting with or without abciximab in acute myocardial infarction: primary endpoint analysis from the CADILLAC trial (abstr). Circulation102(Suppl II):II–664.

(1998) Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol32:1312–1319.

(1998) Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation98:2695–2701.

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